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Surgery in Patients with Gastro-Entero-Pancreatic Neuroendocrine Carcinomas, Neuroendocrine Tumors G3 and High Grade Mixed Neuroendocrine-Non-Neuroendocrine Neoplasms

  • Neuroendocrine Cancers (M Cives, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

In the 2019 WHO guidelines, the classification of gastro-entero-pancreatic neuroendocrine neoplasms (GEP NEN) has changed from one being based on Ki-67 proliferation index alone to one that also includes tumor differentiation. Consequently, GEP NENs are now classified as well-differentiated neuroendocrine tumor (NET), NET G1 (Ki-67 <3%), NET G2 (Ki-67 3–20%) and NET G3 (Ki-67 >20%), and poorly differentiated neuroendocrine carcinoma (NEC) (Ki-67 >20%). It has been suggested that NET G3 should be treated as NET G2 with respect to surgery, while surgical management of NEC should be expanded from local disease to also include patients with advanced disease where curative surgery is possible. High grade mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) have a neuroendocrine and a non-neuroendocrine component mostly with a poor prognosis. All studies evaluating the effect of surgery in NEC and MiNEN are observational and hold a risk of selection bias, which may overestimate the beneficial effect of surgery. Further, only a few studies on the effect of surgery in MiNEN exist. This review aims to summarize the data on the outcome of surgery in patients with GEP NET G3, GEP NEC and high grade MiNEN. The current evidence suggests that patients with NEN G3 and localized disease and NEN G3 patients with metastatic disease where curative surgery can be achieved may benefit from surgery. In patients with MiNEN, it is currently not possible to evaluate on the potential beneficial effect of surgery due to the low number of studies.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Klimstra DS, Kloppel G, La Rosa S RG. Digestive system tumours. In: WHO classification of tumours. In: IARC, Lyon. 5th edition. 2019.

  2. Walter T, Tougeron D, Baudin E, Le Malicot K, Lecomte T, Malka D, et al. Poorly differentiated gastro-entero-pancreatic neuroendocrine carcinomas: are they really heterogeneous? Insights from the FFCD-GTE national cohort. Eur J Cancer. England. 2017;79:158–65.

    Article  CAS  Google Scholar 

  3. Lloyd RV, Osamura RY, Klöppel G RJ. Pathology and genetics of tumours of endocrine organs. Fourth edition—WHO—2017. WHO classification of tumours. 2017;10:320 p.

  4. de Mestier L, Cros J, Neuzillet C, Hentic O, Egal A, Muller N, et al. Digestive system mixed neuroendocrine-non-neuroendocrine neoplasms. Neuroendocrinology. Switzerland. 2017;105(4):412–25.

    Article  CAS  Google Scholar 

  5. Sorbye H, Baudin E, Borbath I, Caplin M, Chen J, Cwikla JB, et al. Unmet needs in high-grade gastroenteropancreatic neuroendocrine neoplasms (WHO G3). Neuroendocrinology. Switzerland. 2019;108(1):54–62.

    Article  CAS  Google Scholar 

  6. Sorbye H, Welin S, Langer SW, Vestermark LW, Holt N, Osterlund P, et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol Off J Eur Soc Med Oncol. England. 2013;24(1):152–60.

    Article  CAS  Google Scholar 

  7. Carlsen EA, Fazio N, Granberg D, Grozinsky-Glasberg S, Ahmadzadehfar H, Grana CM, et al. Peptide receptor radionuclide therapy in gastroenteropancreatic NEN G3: a multicenter cohort study. Endocr Relat Cancer. BioScientifica Ltd. 2019;26(2):227–39.

    Article  CAS  Google Scholar 

  8. Strosberg JR, Coppola D, Klimstra DS, Phan AT, Kulke MH, Wiseman GA, et al. The NANETS consensus guidelines for the diagnosis and management of poorly differentiated (high-grade) extrapulmonary neuroendocrine carcinomas. Pancreas. 2010;39(6):799–800.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Galleberg RB, Knigge U, Tiensuu Janson E, Vestermark LW, Haugvik S-P, Ladekarl M, et al. Results after surgical treatment of liver metastases in patients with high-grade gastroenteropancreatic neuroendocrine carcinomas. Eur J Surg Oncol J Eur Soc Surg Oncol Br Assoc Surg Oncol. England. 2017;43(9):1682–9.

    CAS  Google Scholar 

  10. Merola E, Rinke A, Partelli S, Gress TM, Andreasi V, Kollár A, et al. Surgery with radical intent: is there an indication for G3 neuroendocrine neoplasms? Ann Surg Oncol. United States. 2020;27(5):1348–55.

    Article  Google Scholar 

  11. Merola E, Falconi M, Rinke A, Staettner S, Krendl F, Partelli S, et al. Radical intended surgery for highly selected stage IV neuroendocrine neoplasms G3. Am J Surg. United States. 2020;220(2):284–9.

    Article  Google Scholar 

  12. Mosquera C, Koutlas NJ, Fitzgerald TL. Localized high-grade gastroenteropancreatic neuroendocrine tumors: defining prognostic and therapeutic factors for a disease of increasing clinical significance. Eur J Surg Oncol J Eur Soc Surg Oncol Br Assoc Surg Oncol. England. 2016;42(10):1471–7.

    CAS  Google Scholar 

  13. Pommergaard H-C, Nielsen K, Sorbye H, Federspiel B, Tabaksblat EM, Vestermark LW, et al. Surgery of the primary tumour in 201 patients with high-grade gastroenteropancreatic neuroendocrine and mixed neuroendocrine-non-neuroendocrine neoplasms. J Neuroendocrinol. United States. 2021;33(5):e12967.

    CAS  Google Scholar 

  14. Shi H, Qi C, Meng L, Yao H, Jiang C, Fan M, et al. Do neuroendocrine carcinomas and mixed neuroendocrine-non-neuroendocrine neoplasm of the gastrointestinal tract have the same prognosis? A SEER database analysis of 12,878 cases. Ther Adv Endocrinol Metab. 2020;11:2042018820938304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. van der Veen A, Seesing MFJ, Wijnhoven BPL, de Steur WO, van Berge Henegouwen MI, Rosman C, et al. Management of resectable esophageal and gastric (mixed adeno)neuroendocrine carcinoma: a nationwide cohort study. Eur J Surg Oncol J Eur Soc Surg Oncol Br Assoc Surg Oncol. England. 2018;44(12):1955–62.

    Google Scholar 

  16. Shen C, Chen H, Chen H, Yin Y, Han L, Chen J, et al. Surgical treatment and prognosis of gastric neuroendocrine neoplasms: a single-center experience. BMC Gastroenterol. 2016;16(1):111.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Xie J-W, Sun Y-Q, Feng C-Y, Zheng C-H, Li P, Wang J-B, et al. Evaluation of clinicopathological factors related to the prognosis of gastric neuroendocrine carcinoma. Eur J Surg Oncol J Eur Soc Surg Oncol Br Assoc Surg Oncol. England. 2016;42(10):1464–70.

    Google Scholar 

  18. Crippa S, Partelli S, Bassi C, Berardi R, Capelli P, Scarpa A, et al. Long-term outcomes and prognostic factors in neuroendocrine carcinomas of the pancreas: morphology matters. Surgery. United States. 2016;159(3):862–71.

    Google Scholar 

  19. Feng T, Lv W, Yuan M, Shi Z, Zhong H, Ling S. Surgical resection of the primary tumor leads to prolonged survival in metastatic pancreatic neuroendocrine carcinoma. World J Surg Oncol. 2019;17(1):54.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Partelli S, Inama M, Rinke A, Begum N, Valente R, Fendrich V, et al. Long-term outcomes of surgical management of pancreatic neuroendocrine tumors with synchronous liver metastases. Neuroendocrinology. Switzerland. 2015;102(1–2):68–76.

    Article  CAS  Google Scholar 

  21. Yoshida T, Hijioka S, Hosoda W, Ueno M, Furukawa M, Kobayashi N, et al. Surgery for pancreatic neuroendocrine tumor G3 and carcinoma G3 should be considered separately. Ann Surg Oncol. United States. 2019;26(5):1385–93.

    Article  Google Scholar 

  22. Conte B, George B, Overman M, Estrella J, Jiang Z-Q, Mehrvarz Sarshekeh A, et al. High-grade neuroendocrine colorectal carcinomas: a retrospective study of 100 patients. Clin Colorectal Cancer. 2016;15(2):e1–7.

    Article  PubMed  Google Scholar 

  23. Fields AC, Lu P, Vierra BM, Hu F, Irani J, Bleday R, et al. Survival in patients with high-grade colorectal neuroendocrine carcinomas: the role of surgery and chemotherapy. Ann Surg Oncol. 2019;26(4):1127–33.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Shafqat H, Ali S, Salhab M, Olszewski AJ. Survival of patients with neuroendocrine carcinoma of the colon and rectum: a population-based analysis. Dis Colon Rectum. United States. 2015;58(3):294–303.

    Article  Google Scholar 

  25. Smith JD, Reidy DL, Goodman KA, Shia J, Nash GM. A retrospective review of 126 high-grade neuroendocrine carcinomas of the colon and rectum. Ann Surg Oncol. 2014;21(9):2956–62.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Casas F, Ferrer F, Farrús B, Casals J, Biete A. Primary small cell carcinoma of the esophagus: a review of the literature with emphasis on therapy and prognosis. Cancer. United States. 1997;80(8):1366–72.

    CAS  Google Scholar 

  27. Brenner B, Shah MA, Gonen M, Klimstra DS, Shia J, Kelsen DP. Small-cell carcinoma of the gastrointestinal tract: a retrospective study of 64 cases. Br J Cancer. 2004;90(9):1720–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Halfdanarson TR, Strosberg JR, Tang L, Bellizzi AM, Bergsland EK, O’Dorisio TM, et al. The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Pancreatic Neuroendocrine Tumors. Pancreas. United States. 2020;49(7):863–81.

    Article  Google Scholar 

  29. Haugvik S-P, Janson ET, Österlund P, Langer SW, Falk RS, Labori KJ, et al. Surgical treatment as a principle for patients with high-grade pancreatic neuroendocrine carcinoma: a Nordic multicenter comparative study. Ann Surg Oncol. United States. 2016;23(5):1721–8.

    Article  Google Scholar 

  30. Howe JR, Merchant NB, Conrad C, Keutgen XM, Hallet J, Drebin JA, et al. The North American Neuroendocrine Tumor Society Consensus Paper on the Surgical Management of Pancreatic Neuroendocrine Tumors. Pancreas. 2020;49(1):1–33.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Howe JR, Cardona K, Fraker DL, Kebebew E, Untch BR, Wang Y-Z, et al. The surgical management of small bowel neuroendocrine tumors: consensus guidelines of the North American Neuroendocrine Tumor Society. Pancreas. 2017;46(6):715–31.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ishida M, Sekine S, Fukagawa T, Ohashi M, Morita S, Taniguchi H, et al. Neuroendocrine carcinoma of the stomach: morphologic and immunohistochemical characteristics and prognosis. Am J Surg Pathol. United States. 2013;37(7):949–59.

    Article  Google Scholar 

  33. Panzuto F, Merola E, Pavel ME, Rinke A, Kump P, Partelli S, et al. Stage IV gastro-entero-pancreatic neuroendocrine neoplasms: a risk score to predict clinical outcome. Oncologist. 2017;22(4):409–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Assi HA, Mukherjee S, Kunz PL, Machiorlatti M, Vesely S, Pareek V, et al. Surgery versus surveillance for well-differentiated, nonfunctional pancreatic neuroendocrine tumors: an 11-year analysis of the National Cancer Database. Oncologist. 2020;25(2):e276–83.

    Article  CAS  PubMed  Google Scholar 

  35. Pape U-F, Berndt U, Muller-Nordhorn J, Bohmig M, Roll S, Koch M, et al. Prognostic factors of long-term outcome in gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer. England. 2008;15(4):1083–97.

    Article  Google Scholar 

  36. Janson ET, Knigge U, Dam G, Federspiel B, Grønbaek H, Stålberg P, et al. Nordic guidelines 2021 for diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms. Acta Oncol. England. 2021;60(7):931–41.

    Article  Google Scholar 

  37. Park JY, Ryu M-H, Park YS, Park HJ, Ryoo B-Y, Kim MG, et al. Prognostic significance of neuroendocrine components in gastric carcinomas. Eur J Cancer. England. 2014;50(16):2802–9.

    Article  CAS  Google Scholar 

  38. La Rosa S, Marando A, Sessa F, Capella C. Mixed adenoneuroendocrine carcinomas (MANECs) of the gastrointestinal tract: an update. Cancers (Basel). 2012;4(1):11–30.

    Article  PubMed Central  Google Scholar 

  39. Volante M, Righi L, Asioli S, Bussolati G, Papotti M. Goblet cell carcinoids and other mixed neuroendocrine/nonneuroendocrine neoplasms. Virchows Arch. Germany. 2007;451(Suppl):S61–9.

    Article  Google Scholar 

  40. Apostolidis L, Bergmann F, Jäger D, Winkler EC. Efficacy of topotecan in pretreated metastatic poorly differentiated extrapulmonary neuroendocrine carcinoma. Cancer Med. 2016;5(9):2261–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Frizziero M, Wang X, Chakrabarty B, Childs A, Luong TV, Walter T, et al. Retrospective study on mixed neuroendocrine non-neuroendocrine neoplasms from five European centres. World J Gastroenterol. 2019;25(39):5991–6005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. La Rosa S, Marando A, Furlan D, Sahnane N, Capella C. Colorectal poorly differentiated neuroendocrine carcinomas and mixed adenoneuroendocrine carcinomas: insights into the diagnostic immunophenotype, assessment of methylation profile, and search for prognostic markers. Am J Surg Pathol. United States. 2012;36(4):601–11.

    Article  Google Scholar 

  43. McCusker ME, Coté TR, Clegg LX, Sobin LH. Primary malignant neoplasms of the appendix: a population-based study from the surveillance, epidemiology and end-results program, 1973-1998. Cancer. United States. 2002;94(12):3307–12.

    Google Scholar 

  44. Zheng M, Li T, Li Y, Zhang T, Zhang L, Ma W, et al. Survival profile and prognostic factors for appendiceal mixed neuroendocrine non-neuroendocrine neoplasms: a SEER population-based study. Front Oncol. 2020;10:1660.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Maru DM, Khurana H, Rashid A, Correa AM, Anandasabapathy S, Krishnan S, et al. Retrospective study of clinicopathologic features and prognosis of high-grade neuroendocrine carcinoma of the esophagus. Am J Surg Pathol. United States. 2008;32(9):1404–11.

  46. Basturk O, Tang L, Hruban RH, Adsay V, Yang Z, Krasinskas AM, et al. Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases. Am J Surg Pathol. 2014;38(4):437–47.

    Article  PubMed  PubMed Central  Google Scholar 

  47. La Rosa S, Adsay V, Albarello L, Asioli S, Casnedi S, Franzi F, et al. Clinicopathologic study of 62 acinar cell carcinomas of the pancreas: insights into the morphology and immunophenotype and search for prognostic markers. Am J Surg Pathol. United States. 2012;36(12):1782–95.

    Article  Google Scholar 

  48. Kim J, Lee WJ, Lee SH, Lee KB, Ryu JK, Kim Y-T, et al. Clinical features of 20 patients with curatively resected biliary neuroendocrine tumours. Dig liver Dis Off J Ital Soc Gastroenterol Ital Assoc Study Liver. Netherlands. 2011;43(12):965–70.

  49. Harada K, Sato Y, Ikeda H, Maylee H, Igarashi S, Okamura A, et al. Clinicopathologic study of mixed adenoneuroendocrine carcinomas of hepatobiliary organs. Virchows Arch. Germany. 2012;460(3):281–9.

    Article  Google Scholar 

  50. Laenkholm IT, Langer SW, Andreassen M, Holmager P, Kjaer A, Klose M, et al. A short report of 50 patients with gastroenteropancreatic mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN). Acta Oncol (Stockholm, Sweden). England. 2021;60:808–12.

  51. La Rosa S, Sessa F, Uccella S. Mixed neuroendocrine-nonneuroendocrine neoplasms (MiNENs): unifying the concept of a heterogeneous group of neoplasms. Endocr Pathol. United States. 2016;27(4):284–311.

    Article  CAS  Google Scholar 

  52. Brathwaite S, Yearsley MM, Bekaii-Saab T, Wei L, Schmidt CR, Dillhoff ME, et al. Appendiceal mixed adeno-neuroendocrine carcinoma: a population-based study of the surveillance, epidemiology, and end results registry. Front Oncol. 2016;6:148.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Nießen A, Schimmack S, Weber TF, Mayer P, Bergmann F, Hinz U, et al. Presentation and outcome of mixed neuroendocrine non-neuroendocrine neoplasms of the pancreas. Pancreatol Off J Int Assoc Pancreatol . [et al]. Switzerland; 2021;21(1):224–235.

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Authors and Affiliations

  1. ENETS Neuroendocrine Tumor Centre of Excellence, Copenhagen University Hospital—Rigshospitalet, Copenhagen, Denmark

    Pernille Holmager MD, PhD, Seppo W. Langer MD, PhD, Andreas Kjaer MD, DMSci, Lene Ringholm MD, PhD, Rajendra Singh Garbyal MD, Hans-Christian Pommergaard MD, PhD, Carsten Palnæs Hansen MD, DMSci, Birgitte Federspiel MD, Mikkel Andreassen MD, PhD & Ulrich Knigge MD, DMSci

  2. Department of Endocrinology and Metabolism, Copenhagen University Hospital—Rigshospitalet, Ole Maaløes Vej 24, DK-2200, Copenhagen, Denmark

    Pernille Holmager MD, PhD, Lene Ringholm MD, PhD, Mikkel Andreassen MD, PhD & Ulrich Knigge MD, DMSci

  3. Department of Oncology, Copenhagen University Hospital—Rigshospitalet, Copenhagen, Denmark

    Seppo W. Langer MD, PhD

  4. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

    Seppo W. Langer MD, PhD & Mikkel Andreassen MD, PhD

  5. Department of Clinical Physiology, Nuclear Medicine and PET and Cluster for Molecular Imaging, Copenhagen University Hospital—Rigshospitalet, Copenhagen, Denmark

    Andreas Kjaer MD, DMSci

  6. Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

    Andreas Kjaer MD, DMSci & Birgitte Federspiel MD

  7. Department of Pathology, Copenhagen University Hospital—Rigshospitalet, Copenhagen, Denmark

    Rajendra Singh Garbyal MD

  8. Department of Surgery and Transplantation, Copenhagen University Hospital—Rigshospitalet, Copenhagen, Denmark

    Hans-Christian Pommergaard MD, PhD, Carsten Palnæs Hansen MD, DMSci & Ulrich Knigge MD, DMSci

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  1. Pernille Holmager MD, PhD
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Pernille Holmager declares that she has no conflict of interest. Seppo Langer declares that he has no conflict of interest. Andreas Kjaer declares that he has no conflict of interest. Lene Ringholm declares that she has no conflict of interest. Rajendra Singh Garbyal declares that he has no conflict of interest. Hans-Christian Pommergaard declares that he has no conflict of interest. Carsten Palnaes Hansen declares that he has no conflict of interest. Birgitte Federspiel declares that she has no conflict of interest. Mikkel Andreassen declares that he has no conflict of interest. Ulrich Knigge declares that he has no conflict of interest.

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Holmager, P., Langer, S.W., Kjaer, A. et al. Surgery in Patients with Gastro-Entero-Pancreatic Neuroendocrine Carcinomas, Neuroendocrine Tumors G3 and High Grade Mixed Neuroendocrine-Non-Neuroendocrine Neoplasms. Curr. Treat. Options in Oncol. 23, 806–817 (2022). https://doi.org/10.1007/s11864-022-00969-x

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